Abstract

The founder germline TP53 mutation, p.R337H, was detected in South and Southern Brazil in families with Li-Fraumeni Syndrome (LFS). The aim of this study was to estimate the burden and patterns of cancer in p.R337H carriers and other germline TP53 mutations. We analyzed data on 539 individuals from the LFS/LFL database from A.C. Camargo Cancer Center in São Paulo, Brazil and compared to International Agency for Research on Cancer (IARC) germline TP53 mutations database (R17). A total of 144 p.R337H carriers have developed 147 cancers (16.7% multiple primaries). The most frequent malignancies were soft tissue sarcoma (STS; 25.9%), breast cancer (24.5%) and adrenocortical carcinoma (ACC; 17.7%). Compared to IARC database, p.R337H carriers had a higher risk of ACC and STS, a lower risk of brain tumors and osteosarcomas (P<0.01). Patients with p.R337H were at risk for developing thyroid and kidney cancers. The median age at diagnosis was 43 years in p.R337H carriers, 30 in other mutations carriers and 65 in the general population. The overall penetrance was similar in both groups until age 12 years. Penetrance was lower in p.R337H carriers (27% at 30 years, 55% at 60 years). The lifetime penetrance was significantly higher in females (79%) than in males (48%). p.R337H-associated disease resembles LFS until age 12, and then diverges, with differences in men and women and a predisposition to cancers that are not part of the LFS spectrum. These observations suggest that p.R337H could predispose to a variant form of LFS.